Abstract
Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) to induce experimental diabetes in AD transgenic mice (5XFAD model) and investigated how insulin deficiency affects the β-amyloidogenic processing of amyloid precursor protein (APP). Two and half months after 5XFAD mice were treated with STZ (90 mg/kg, i.p., once daily for two consecutive days), they showed significant reductions in brain insulin levels without changes in insulin receptor expression. Concentrations of cerebral amyloid-β peptides (Aβ40 and Aβ42) were significantly increased in STZ-treated 5XFAD mice as compared with vehicle-treated 5XFAD controls. Importantly, STZ-induced insulin deficiency upregulated levels of both β-site APP cleaving enzyme 1 (BACE1) and full-length APP in 5XFAD mouse brains, which was accompanied by dramatic elevations in the β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA levels were not affected, whereas phosphorylation of the translation initiation factor eIF2α, a mechanism proposed to mediate the post-transcriptional upregulation of BACE1, was significantly elevated in STZ-treated 5XFAD mice. Meanwhile, levels of GGA3, an adapter protein responsible for sorting BACE1 to lysosomal degradation, are indistinguishable between STZ- and vehicle-treated 5XFAD mice. Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains. Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia among the elderly population
Consistent with epidemiological investigations showing that diabetes is an important risk factor for sporadic AD, a growing body of evidence indicates defective insulin signaling in AD brains [6,7,8,9]
We first demonstrated that protein levels of b-site APP cleaving enzyme 1 (BACE1), a key enzyme that initiates the production of Ab peptides from their parent molecule amyloid precursor protein (APP), are significantly elevated in STZ-treated 5XFAD mice
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia among the elderly population. It seems reasonable to hypothesize that sporadic AD represents a form of diabetes that selectively involves the brain and has the disturbed insulin signaling pathway in common with type 1 and type 2 diabetes mellitus [11]. This hypothesis is supported by recent findings that analogue compounds for the incretin hormone glucagon-like peptide-1 (GLP-1), which facilitate endogenous insulin release and are used to treat type 2 diabetes, reduce Ab accumulation and rescue impairments in hippocampal synaptic plasticity and spatial learning and memory in transgenic mouse models of AD [12,13,14]. It has been demonstrated that soluble Ab oligomers produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway [17,18,19,20]
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